Naphathalene derivatives which bind to the ep4 receptor

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable derivatives thereof bind with high affinity to the EP4 receptor and are of use in the treatment of prevention of conditions such as a pain, inflammatory, immunological, bone, neurodegenerative or renal disorder.

[0001] This invention relates to naphthalene derivatives, to processesfor their preparation, to pharmaceutical compositions containing themand to their use in medicine.

[0002] The EP4 receptor is a 7-transmembrane receptor and its naturalligand is the prostaglandin PGE₂. PGE₂ also has affinity for the otherEP receptors (types EP1, EP2 and EP3). The EP4 receptor is associatedwith smooth muscle relaxation, inflammation, lymphocyte differentiation,bone metabolism processes, allergic activities, promotion of sleep,renal regulation and gastric or enteric mucus secretion. We have nowfound a novel group of compounds which bind with high affinity to theEP4 receptor.

[0003] The invention thus provides compounds of the formula (I)

[0004] and pharmaceutically acceptable derivatives thereof in which:

[0005] a=0 or 1;

[0006] b=0 to 3;

[0007] R¹ is H, halogen, C₁₋₆alkyl, S—C₁₋₆alkyl, C₁₋₆alkoxy, OCF₃,OCH₂CF₃, O-cyclopropyl, OCH₂-cyclopropyl, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, NO₂, OH, CH₂OC₁₋₆alkyl or CH₂OH;

[0008] each R² is independently selected from C₁₋₄alkyl;

[0009] R³ is H or O;

[0010] R⁴ is H or C₁₋₆alkyl;

[0011] R⁵ and R⁶ are each independently selected from H, halogen,C₁₋₃alkyl, or are taken together to form a cyclopropyl ring;

[0012] R⁷ to R¹⁰ are each independently selected from H, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one or more fluorine atoms,O-cyclopropyl, OCH₂-cyclopropyl, S—C₁₋₆alkyl, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, halogen, NO₂, OH, CH₂OC₁₋₆alkyl, CH₂OH;

[0013] R¹¹ is selected from H, OH, halogen, dihalogen, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, C₁₋₆alkyl, C₁₋₆dialkyl, C₁₋₆alkoxy, NHCO(C₁₋₆alkyl), or═O;

[0014] R¹² is selected from H, C₁₋₆alkyl, phenyl, phenyl substituted byone or more R¹³, phenyl fused to a heterocycle, naphthyl, naphthylsubstituted by one or more R¹³, C₄₋₇cycloalkyl, C₄₋₇cycloalkyl fused toa benzene ring, OCOC₁₋₆alkyl, heteroaryl or heteroaryl substituted byone or more R¹³;

[0015] R¹³ is halogen, C₁₋₆alkyl, C₁₋₆alkyl substituted by one or morefluorine atoms, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one or morefluorine atoms, phenyl, CN, CO₂H, CO₂C₁₋₆alkyl, OH, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, S(O)_(n)C₁₋₆alkyl where n is 0, 1 or 2, SO₂N(C₁₋₆alkyl)₂,CONH₂, CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂, COC₁₋₆alkyl, benzyloxy, CH₂CO₂H,CH₂CO₂C₁₋₆alkyl, NO₂ or NHCO(C₁₋₆alkyl);

[0016]

is a single bond or, when R³ is O a double bond.

[0017] By pharmaceutically acceptable derivative is meant anypharmaceutically acceptable salt or solvate of the compounds of formula(I), or any other compound which upon administration to the recipient iscapable of providing (directly or indirectly) a compound of formula (I)or an active metabolite or residue thereof.

[0018] It will be appreciated by those skilled in the art that thecompounds of formula (I) may be modified to provide pharmaceuticallyacceptable derivatives thereof at any of the functional groups in thecompounds, and that the compounds of formula (I) may be derivatised atmore than one position.

[0019] It will be appreciated that, for pharmaceutical use, the saltsreferred to above will be physiologically acceptable salts, but othersalts may find use, for example in the preparation of compounds offormula (I) and the physiological acceptable salts thereof.

[0020] Pharmaceutically acceptable salts include those described byBerge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Suitablepharmaceutically acceptable salts include: acid addition salts formedwith inorganic acids or organic acids, preferably inorganic acids e.g.hydrochlorides, hydrobromides, sulphates and acetates; and alkali metalsalts, formed from the addition of alkali metal bases, such as alkalimetal hydroxides e.g. sodium salts. Further representative examples ofpharmaceutically acceptable salts include those formed from maleic,fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic,methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic,citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic,phosphoric and nitric acids.

[0021] The term ‘halogen’ is used to represent fluorine, chlorine,bromine or iodine.

[0022] The term ‘alkyl’ as a group or part of a group means a straightor branched chain alkyl group, for example a methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl or t-butyl group.

[0023] The term ‘alkoxy’ as a group or as part of a group means astraight or branched chain alkyl group having an oxygen atom attached tothe chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, s-butoxy or t-butoxy group.

[0024] The term ‘heterocycle’ as a group or as part of a group means anon-aromatic five or six membered ring which contains from 1 to 3heteroatoms selected from nitrogen, oxygen or sulfur and which may beoptionally substituted with one or more C₁₋₆alkyl groups. Examples ofsuitable heterocycles include 1,4-dioxane, 1,3-dioxolane and2,2-dimethyl-1,3-dioxolane.

[0025] The term ‘heteroaryl’ as a group or as part of a group means amonocyclic five or six membered aromatic ring, or a fused bicyclicaromatic ring system comprising two of such monocyclic five or sixmembered aromatic rings. These heteroaryl rings contain one or moreheteroatoms selected from nitrogen, oxygen or sulfur, where N-oxides,sulfur oxides and sulfur dioxides are permissible heteroatomsubstitutions. Examples of “heteroaryl” used herein include furan,thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole,oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine,pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole,and indazole.

[0026] In one aspect of the invention a=1.

[0027] In another aspect of the invention b=1.

[0028] In another aspect of the Invention R¹ is at the 6-position of thenaphthalene ring, as defined in formula (I).

[0029] In another aspect of the invention R¹ is H or halogen.

[0030] In another aspect of the invention R¹ is H or bromine.

[0031] In another aspect of the invention each R² is ethyl.

[0032] In another aspect of the invention R⁴ is H or methyl.

[0033] In another aspect of the invention R⁵ and R⁶ are eachindependently selected from H, chlorine, methyl or ethyl, or are takentogether to form a cyclopropyl ring.

[0034] In another aspect of the invention each of R⁷ to R¹¹ is hydrogen.

[0035] In another aspect of the invention R¹² is selected from C₁₋₆alkyl(preferably methyl), phenyl, phenyl substituted by one or more R¹³,phenyl fused to a heterocycle selected from 1,4dioxane, 1,3-dioxolaneand 2,2-dimethyl-1,3-dioxolane, naphthyl, naphthyl substituted by one ormore C₁₋₆alkoxy (preferably methoxy), thiophene, thiazole, thiazolesubstituted by one or more C₁₋₆alkyl (preferably methyl), indole, indolesubstituted by one or more C₁₋₆alkyl (preferably methyl), or benzofuran.

[0036] In another aspect of the invention R¹³ is halogen, C₁₋₆alkyl,C₁₋₆alkyl substituted by one or more fluorine atoms, C₁₋₆alkoxy,C₁₋₆alkoxy substituted by one or more fluorine atoms, phenyl, CN,CO₂C₁₋₆alkyl, OH, N(C₁₋₆alkyl)₂, SO₂N(C₁₋₆alkyl)₂, benzyloxy, CH₂CO₂H,CH₂CO₂C₁₋₆alkyl or NO₂.

[0037] In another aspect of the invention R¹³ is chlorine, fluorine,methyl, ethyl, i-propyl, i-butyl, CF₃, methoxy, ethoxy, OCF₃, phenyl,CN, CO₂CH₃, OH, NMe₂, SO₂NMe₂, benzyloxy, CH₂CO₂H, CH₂CO₂Me or NO₂.

[0038] In another aspect of the invention R¹² is phenyl substituted byone or two groups selected from chlorine (preferably as a substituent inthe 2 or 4 position of the phenyl ring), fluorine (preferably as asubstituent in the 2, 3, 4, or 2 and 5 positions of the phenyl ring),methyl (preferably as a substituent in the 2, 3 or 4 position of thephenyl ring, or, if two substituents are present, in the 2 and 5, or 2and 6 positions of the phenyl ring), ethyl (preferably as a substituentin the 4 position of the phenyl ring), i-propyl (preferably as asubstituent in the 4 position of the phenyl ring), i-butyl (preferablyas a substituent in the 4 position of the phenyl ring), methoxy(preferably as a substituent in the 2, 3 or 4 position of the phenylring, or, if two substituents are present, in the 2 and 3, 3 and 4, 2and 5, or 3 and 5 positions of the phenyl ring), ethoxy (preferably as adisubstituent in the 3 and 4 positions of the phenyl ring), OCF₃(preferably as a substituent in the 3 or 4 position of the phenyl ring),phenyl (preferably as a substituent in the 4 position of the phenylring), benzyloxy (preferably as a substituent in the 3 position of thephenyl ring), or CH₂CO₂Me (preferably as a substituent in the 2 positionof the phenyl ring).

[0039] In another aspect of the invention R¹² is phenyl substituted byone or two groups selected from methyl (preferably substituted in the 4position of the phenyl ring) or methoxy (preferably substituted in the2, 3 or 4 position of the phenyl ring, or, if two substituents arepresent, in the 2 and 3 or 3 and 4 positions of the phenyl ring).

[0040] It is to be understood that the present invention covers allcombinations of particular aspects of the invention as describedhereinabove.

[0041] In a particular aspect of the invention there is provided a groupof compounds of formula (I) (group A) wherein: a is 1, b is 1, R¹ is Hor bromine; each R² is ethyl; R³ is H; R⁴ is H or methyl; R⁵ and R⁶ areeach independently selected from H, halogen, C₁₋₃alkyl, or are takentogether to form a cyclopropyl ring; each of R⁷ to R¹ is hydrogen; R¹²is selected from H, C₁₋₆alkyl, phenyl, phenyl substituted by one or moreR¹³, phenyl fused to a heterocycle, naphthyl, naphthyl substituted byone or more R¹³, C₄₋₇cycloalkyl, C₄₋₇cycloalkyl fused to a benzene ring,OCOC₁₋₆alkyl, heteroaryl or heteroaryl substituted by one or more R¹³;R¹³ is halogen, C₁₋₆alkyl, C₁₋₆alkyl substituted by one or more fluorineatoms, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one or more fluorine atoms,phenyl, CN, CO₂H, CO₂C₁₋₆alkyl, OH, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂,S(O)_(n)C₁₋₆alkyl where n is 0, 1 or 2, SO₂N(C₁₋₆alkyl)₂, CONH₂,CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂, COC₁₋₆alkyl, benzyloxy, CH₂CO₂H,CH₂CO₂C₁₋₆alkyl, NO₂ or NHCO(C₁₋₆alkyl).

[0042] Within group A, there is provided a further group of compounds(group A1) wherein: R¹ is H; each R² is ethyl; R³ is H; R⁴ is H; R⁵ andR⁶ are each independently selected from H, chlorine, methyl or ethyl, orare taken together to form a cyclopropyl ring; each of R⁷ to R¹¹ ishydrogen; R¹² is selected from phenyl, phenyl substituted by one or moreR¹³, phenyl fused to a heterocycle, naphthyl, naphthyl substituted byone or more C₁₋₆alkoxy, heteroaryl or heteroaryl substituted by one ormore C₁₋₆alkyl; R¹³ is halogen, C₁₋₆alkyl, C₁₋₆alkyl substituted by oneor more fluorine atoms, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one ormore fluorine atoms, phenyl, CN, CO₂H, CO₂C₁₋₆alkyl, OH, NH₂,NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, S(O)_(n)C₁₋₆alkyl where n is 0, 1 or 2,SO₂N(C₁₋₆alkyl)₂, CONH₂, CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂, COC₁₋₆alkyl,benzyloxy, CH₂CO₂H, CH₂CO₂C₁₋₆alkyl, NO₂ or NHCO(C₁₋₆alkyl).

[0043] Within group A there is provided a further group of compoundswherein R¹ is at the 6-position of the naphthalene ring, as defined informula (I).

[0044] In a particular aspect of the invention there is provided a groupof compounds of formula (I) (group B) wherein: a is 1, b is 1, R¹ is Hor bromine; each R² is ethyl; R³ is O; R⁴ is H or methyl; R⁵ and R⁶ areeach independently selected from H, halogen, C₁₋₃alkyl, or are takentogether to form a cyclopropyl ring; each of R⁷ to R¹¹ is hydrogen; R¹²is selected from H, C₁₋₆alkyl, phenyl, phenyl substituted by one or moreR¹³, phenyl fused to a heterocycle, naphthyl, naphthyl substituted byone or more R¹³, C₄₋₇cycloalkyl, C₄₋₇cycloalkyl fused to a benzene ring,OCOC₁₋₆alkyl, heteroaryl or heteroaryl substituted by one or more R¹³;R¹³ is halogen, C₁₋₆alkyl, C₁₋₆alkyl substituted by one or more fluorineatoms, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one or more fluorine atoms,phenyl, CN, CO₂H, CO₂C₁₋₆alkyl, OH, NH₂, NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂,S(O)_(n)C₁₋₆alkyl where n is 0, 1 or 2, SO₂N(C₁₋₆alkyl)₂, CONH₂,CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂, COC₁₋₆alkyl, benzyloxy, CH₂CO₂H,CH₂CO₂C₁₋₆alkyl, NO₂ or NHCO(C₁₋₆alkyl).

[0045] Within group B, there is provided a further group of compounds(group B1) wherein: R¹ is H; each R² is ethyl; R³ is O; R⁴ is H; R⁵ andR⁶ are each independently selected from H, chlorine, methyl or ethyl, orare taken together to form a cyclopropyl ring; each of R⁷ to R¹¹ ishydrogen; R¹² is selected from phenyl, phenyl substituted by one or moreR¹³, phenyl fused to a heterocycle, naphthyl, naphthyl substituted byone or more C₁₋₆alkoxy, heteroaryl or heteroaryl substituted by one ormore C₁₋₆alkyl; R¹³ is halogen, C₁₋₆alkyl, C₁₋₆alkyl substituted by oneor more fluorine atoms, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one ormore fluorine atoms, phenyl, CN, CO₂H, CO₂C₁₋₆alkyl, OH, NH₂,NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, S(O)_(n)C₁₋₆alkyl where n is 0, 1 or 2,SO₂N(C₁₋₆alkyl)₂, CONH₂, CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂, COC₁₋₆alkyl,benzyloxy, CH₂CO₂H, CH₂CO₂C₁₋₆alkyl, NO₂ or NHCO(C₁₋₆alkyl).

[0046] Within group B there is provided a further group of compoundswherein R¹ is at the 6-position of the naphthalene ring, as defined informula (I).

[0047] It is to be understood that the present invention encompasses allisomers of formula (I) and their pharmaceutically acceptablederivatives, including all geometric, tautomeric and optical forms, andmixtures thereof (e.g. racemic mixtures).

[0048] In one aspect the invention provides the following compounds andpharmaceutically acceptable derivatives thereof:

[0049]1-[4(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-[(4-methoxyphenyl)acetyl]methanesulfonamide,

[0050]1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-[(2-methoxyphenyl)acetyl]methanesulfonamide,

[0051]1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-[(2,3-dimethoxyphenyl)acetyl]methanesulfonamide,

[0052]1-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-[(3,4-dimethoxyphenyl)acetyl]methanesulfonamide,

[0053]1-[4-(4,9diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-[(3-methoxyphenyl)acetyl]methanesulfonamide,

[0054]1-[4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol2-yl)phenyl]-N-[(3,4-dimethoxyphenyl)acetyl]methanesulfonamide,

[0055]1-[4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-[(4-methylphenyl)acetyl]methanesulfonamide,and

[0056]1-[4(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-[(2-methoxyphenyl)acetyl]methanesulfonamide.

[0057] Since the compounds of the present invention, in particularcompounds of formula (I), are intended for use in pharmaceuticalcompositions, it will be understood that they are each provided insubstantially pure form, for example at least 50% pure, more suitably atleast 75% pure and preferably at least 95% pure (% are on a wt/wtbasis). Impure preparations of the compounds of formula (I) may be usedfor preparing the more pure forms used in the pharmaceuticalcompositions. Although the purity of intermediate compounds of thepresent invention is less critical, it will be readily understood thatthe substantially pure form is preferred as for the compounds of formula(I). Preferably, whenever possible, the compounds of the presentinvention are obtained in crystalline form.

[0058] When some of the compounds of this invention are allowed tocrystallise or are recrystallised from organic solvents, solvent ofcrystallisation may be present in the crystalline product. Thisinvention includes within its scope such solvates.

[0059] Similarly, some of the compounds of this invention may becrystallised or recrystallised from solvents containing water. In suchcases water of hydration may be formed. This invention includes withinits scope stoichiometric hydrates as well as compounds containingvariable amounts of water that may be produced by processes such aslyophilisation. In addition, different crystallisation conditions maylead to the formation of different polymorphic forms of crystallineproducts. This invention includes within its scope all polymorphic formsof the compounds of formula (I).

[0060] The compounds of the invention bind to the EP4 receptor and aretherefore useful in treating EP4 receptor mediated diseases.

[0061] In view of their ability to bind to the EP4 receptor, thecompounds of the invention are useful in the treatment of the disordersthat follow. Thus, the compounds of formula (I) are useful asanalgesics. For example they are useful in the treatment of chronicarticular pain (e.g. rheumatoid arthritis, osteoarthritis, rheumatoidspondylitis, gouty arthritis and juvenile arthritis) including theproperty of disease modification and joint structure preservation;musculoskeletal pain; lower back and neck pain; sprains and strains;neuropathic pain; sympathetically maintained pain; myositis; painassociated with cancer and fibromyalgia; pain associated with migraine;pain associated with influenza or other viral infections, such as thecommon cold; rheumatic fever; pain associated with functional boweldisorders such as non-ulcer dyspepsia, non-cardiac chest pain andirritable bowel syndrome; pain associated with myocardial ischemia; postoperative pain; headache; toothache; and dysmenorrhea.

[0062] The compounds of the invention are particularly useful in thetreatment of neuropathic pain. Neuropathic pain syndromes can developfollowing neuronal injury and the resulting pain may persist for monthsor years, even after the original injury has healed. Neuronal injury mayoccur in the peripheral nerves, dorsal roots, spinal cord or certainregions in the brain. Neuropathic pain syndromes are traditionallyclassified according to the disease or event that precipitated them.Neuropathic pain syndromes include: diabetic neuropathy; sciatica;non-specific lower back pain; multiple sclerosis pain; fibromyalgia;HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia;and pain resulting from physical trauma, amputation, cancer, toxins orchronic inflammatory conditions. These conditions are difficult to treatand although several drugs are known to have limited efficacy, completepain control is rarely achieved. The symptoms of neuropathic pain areincredibly heterogeneous and are often described as spontaneous shootingand lancinating pain, or ongoing, burning pain. In addition, there ispain associated with normally non-painful sensations such as “pins andneedles” (paraesthesias and dysesthesias), increased sensitivity totouch (hyperesthesia), painful sensation following innocuous stimulation(dynamic, static or thermal allodynia), increased sensitivity to noxiousstimuli (thermal, cold, mechanical hyperalgesia), continuing painsensation after removal of the stimulation (hyperpathia) or an absenceof or deficit in selective sensory pathways (hypoalgesia).

[0063] The compounds of formula (I) are also useful in the treatment ofinflammation, for example in the treatment of skin conditions (e.g.sunburn, bums, eczema, dermatitis, psoriasis); ophthalmic diseases suchas glaucoma, retinitis, retinopathies, uveitis and of acute injury tothe eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma,bronchitis, emphysema, allergic rhinitis, respiratory distress syndromepigeon fanciers disease, farmer's lung, COPD); gastrointestinal tractdisorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis,gastritis varialoforme, ulcerative colitis, coeliac disease, regionalileitis, irritable bowel syndrome, inflammatory bowel disease,gastrointestinal reflux disease); organ transplantation; otherconditions with an inflammatory component such as vascular disease,migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin'sdisease, sclerodoma, myaesthenia gravis, multiple sclerosis,sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis,gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus,polymyositis, tendinitis, bursitis, and Sjogren's syndrome.

[0064] The compounds of formula (I) are also useful in the treatment ofimmunological diseases such as autoimmune diseases, immunologicaldeficiency diseases or organ transplantation. The compounds of formula(I) are also effective in increasing the latency of HIV infection.

[0065] The compounds of formula (I) are also useful in the treatment ofdiseases of abnormal platelet function (e.g. occlusive vasculardiseases).

[0066] The compounds of formula (I) are also useful for the preparationof a drug with diuretic action.

[0067] The compounds of formula (I) are also useful in the treatment ofimpotence or erectile dysfunction.

[0068] The compounds of formula (I) are also useful in the treatment ofbone disease characterised by abnormal bone metabolism or resorptionsuch as osteoporosis (especially postmenopausal osteoporosis),hyper-calcemia, hyperparathyroidism, Paget's bone diseases, osteolysis,hypercalcemia of malignancy with or without bone metastases, rheumatoidarthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, cancercacchexia, calculosis, lithiasis (especially urolithiasis), solidcarcinoma, gout and ankylosing spondylitis, tendinitis and bursitis. Ina further aspect compounds of formula (I) may be useful in inhibitingbone resorption and/or promoting bone generation.

[0069] The compounds of formula (I) are also useful for attenuating thehemodynamic side effects of NSAIDs and COX-2 inhibitors.

[0070] The compounds of formula (I) are also useful in the treatment ofcardiovascular diseases such as hypertension or myocardiac ischemia;functional or organic venous insufficiency; varicose therapy;haemorrhoids; and shock states associated with a marked drop in arterialpressure (e.g. septic shock).

[0071] The compounds of formula (I) are also useful in the treatment ofneurodegenerative diseases and neurodegeneration such as dementia,particularly degenerative dementia (including senile dementia,Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson'sdisease and Creutzfeldt-Jakob disease, ALS, motor neuron disease);vascular dementia (including multi-infarct dementia); as well asdementia associated with intracranial space occupying lesions; trauma;infections and related conditions (including HIV infection); metabolism;toxins; anoxia and vitamin deficiency; and mild cognitive impairmentassociated with ageing, particularly Age Associated Memory Impairment.

[0072] The compounds of formula (I) are also useful in the treatment ofneuroprotection and in the treatment of neurodegeneration followingstroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinalcord injury or the like.

[0073] The compounds of formula (I) are also useful in the treatment oftinnitus.

[0074] The compounds of formula (I) are also useful in preventing orreducing dependence on, or preventing or reducing tolerance or reversetolerance to, a dependence—inducing agent. Examples of dependenceinducing agents include opioids (e.g. morphine), CNS depressants (e.g.ethanol), psychostimulants (e.g. cocaine) and nicotine.

[0075] The compounds of formula (I) are also useful in the treatment ofcomplications of Type 1 diabetes (e.g. diabetic microangiopathy,diabetic retinopathy, diabetic nephropathy, macular degeneration,glaucoma), nephrotic syndrome, aplastic anaemia, uveitis, Kawasakidisease and sarcoidosis.

[0076] The compounds of formula (I) are also useful in the treatment ofkidney dysfunction (nephritis, particularly mesangial proliferativeglomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis,cirrhosis), gastrointestinal dysfunction (diarrhoea) and colon cancer.

[0077] It is to be understood that reference to treatment includes bothtreatment of established symptoms and prophylactic treatment, unlessexplicitly stated otherwise.

[0078] According to a further aspect of the invention, we provide acompound of formula (I) or a pharmaceutically acceptable derivativethereof for use in human or veterinary medicine.

[0079] According to another aspect of the invention, we provide acompound of formula (I) or a pharmaceutically acceptable derivativethereof for use in the treatment of a condition which is mediated by theaction of PGE₂ at EP4 receptors.

[0080] According to a further aspect of the invention, we provide amethod of treating a human or animal subject suffering from a conditionwhich is mediated by the action of PGE₂ at EP4 receptors which comprisesadministering to said subject an effective amount of a compound offormula (I) or a pharmaceutically acceptable derivative thereof.

[0081] According to a further aspect of the invention we provide amethod of treating a human or animal subject suffering from a pain,inflammatory, immunological, bone, neurodegenerative or renal disorder,which method comprises administering to said subject an effective amountof a compound of formula (I) or a pharmaceutically acceptable derivativethereof.

[0082] According to another aspect of the invention, we provide the useof a compound of formula (I) or a pharmaceutically acceptable derivativethereof for the manufacture of a therapeutic agent for the treatment ofa condition which is mediated by the action of PGE₂ at EP4 receptors.

[0083] According to another aspect of the invention we provide the useof a compound of formula (I) or a pharmaceutically acceptable derivativethereof for the manufacture of a therapeutic agent for the treatment orprevention of a condition such as a pain, inflammatory, immunological,bone, neurodegenerative or renal disorder.

[0084] The compounds of formula (I) and their pharmaceuticallyacceptable derivatives are conveniently administered in the form ofpharmaceutical compositions. Such compositions may conveniently bepresented for use in conventional manner in admixture with one or morephysiologically acceptable carriers or excipients.

[0085] Thus, in another aspect of the invention, we provide apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable derivative thereof adapted for use in humanor veterinary medicine.

[0086] The compounds of formula (I) and their pharmaceuticallyacceptable derivatives may be formulated for administration in anysuitable manner. They may, for example, be formulated for topicaladministration or administration by inhalation or, more preferably, fororal, transdermal or parenteral administration. The pharmaceuticalcomposition may be in a form such that it can effect controlled releaseof the compounds of formula (I) and their pharmaceutically acceptablederivatives.

[0087] For oral administration, the pharmaceutical composition may takethe form of, for example, tablets (including sub-lingual tablets),capsules, powders, solutions, syrups or suspensions prepared byconventional means with acceptable excipients.

[0088] For transdermal administration, the pharmaceutical compositionmay be given in the form of a transdermal patch, such as a transdermaliontophoretic patch.

[0089] For parenteral administration, the pharmaceutical composition maybe given as an injection or a continuous infusion (e.g. intravenously,intravascularly or subcutaneously). The compositions may take such formsas suspensions, solutions or emulsions in oily or aqueous vehicles andmay contain formulatory agents such as suspending, stabilising and/ordispersing agents. For administration by injection these may take theform of a unit dose presentation or as a multidose presentationpreferably with an added preservative.

[0090] Alternatively for parenteral administration the active ingredientmay be in powder form for reconstitution with a suitable vehicle.

[0091] The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

[0092] The EP4 receptor compounds for use in the instant invention maybe used in combination with other therapeutic agents, for example COX-2inhibitors, such as celecoxib, rofecoxib, valdecoxib or parecoxib;5-lipoxygenase inhibitors; NSAID's, such as diclofenac, indomethacin,nabumetone or ibuprofen; leukotriene receptor antagonists; DMARD's suchas methotrexate; adenosine A1 receptor agonists; sodium channelblockers, such as lamotrigine; NMDA receptor modulators, such as glycinereceptor antagonists; gabapentin and related compounds; tricyclicantidepressants such as amitriptyline; neurone stabilising antiepilepticdrugs; mono-aminergic uptake inhibitors such as venlafaxine; opioidanalgesics; local anaesthetics; 5HT₁ agonists, such as triptans, forexample sumatriptan, naratriptan, zolmitriptan, eletriptan,frovatriptan, almotriptan or rizatriptan; EP1 receptor ligands; EP2receptor ligands; EP3 receptor ligands; EP1 antagonists; EP2 antagonistsand EP3 antagonists. When the compounds are used in combination withother therapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

[0093] The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablederivative thereof together with a further therapeutic agent or agents.

[0094] The combinations referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical formulations comprising a combination as defined abovetogether with a pharmaceutically acceptable carrier or excipientcomprise a further aspect of the invention. The individual components ofsuch combinations may be administered either sequentially orsimultaneously in separate or combined pharmaceutical formulations.

[0095] When a compound of formula (I) or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art.

[0096] A proposed daily dosage of compounds of formula (I) or theirpharmaceutically acceptable salts for the treatment of man is from 0.01to 10 mg/kg body weight per day and more particularly 0.1 to 3 mg/kgbody weight per day, calculated as the free base, which may beadministered as a single or divided dose, for example one to four timesper day The dose range for adult human beings is generally from 8 to1000 mg/day, such as from 20 to 800 mg/day, preferably 35 to 200 mg/day,calculated as the free base.

[0097] The precise amount of the compounds of formula (I) administeredto a host, particularly a human patient, will be the responsibility ofthe attendant physician. However, the dose employed will depend on anumber of factors including the age and sex of the patient, the precisecondition being treated and its severity, and the route ofadministration.

[0098] Compounds of formula (I) and pharmaceutically acceptablederivatives thereof may be prepared by any method known in the art forthe preparation of compounds of analogous structure.

[0099] Compounds of formula (I) and pharmaceutically acceptablederivatives thereof may be prepared by a process which comprises:

[0100] (A), coupling a sulfonamide of formula (II)

[0101] or a protected derivative thereof with an acid chloride offormula (III)

[0102] or a protected derivative thereof; or

[0103] (B), coupling a sulfonamide of formula (II)

[0104] or a protected derivative thereof with an acid of formula (IV)

[0105] or a protected derivative thereof; or

[0106] (C), interconversion of a compound of formula (I) into anothercompound of formula (I); or

[0107] (D), deprotecting a protected derivative of compound of formula(I); and

[0108] optionally converting compounds of formula (I) prepared by anyone of the processes (A) to (D) into pharmaceutically acceptablederivatives thereof.

[0109] Suitable methods for the preparation of compounds of formula (I)and pharmaceutically acceptable derivatives thereof are described below,and form a further aspect of the invention. In the Schemes that follow,R¹ to R¹² are as defined in formula (I) above unless otherwise stated;DMF is dimethylformamide; DCM is dichloromethane; TFA is trifluoroaceticacid; DMAP is dimethylaminopyridine; Ac is acetyl; Hal is halogen.

[0110] Referring to Scheme 1 that follows, compounds of formula (I),wherein a is 1, R³ is O and R⁴ is H, may be prepared by coupling acompound of formula (II) with an acid chloride of formula (III) in thepresence of a non-nucleophilic base, such as potassium carbonate orDMAP, in a suitable aprotic solvent such as acetone or toluene. In oneembodiment of Scheme 1, potassium carbonate is added to a solutioncomprising a compound of formula (II) and an acid chloride of formula(111) in acetone. The reaction mixture is then heated at about 80° C.under nitrogen for about 18 h. The reaction is then allowed to cool toambient temperature and filtered to remove remaining solid. The filtrateis acidified using 2N hydrochloric acid and then diluted with water. Theprecipitate is then filtered off and triturated with diethylether togive a compound of formula (I), wherein a is 1, R³ is O and R⁴ is H, asa solid. In another embodiment of Scheme 1, DMAP is added to a solutioncomprising a compound of formula (II) and an acid chloride of formula(III) in toluene. The reaction mixture is then heated at about 120° C.under nitrogen for about 18 h. The reaction is then allowed to cool toambient temperature and concentrated in vacuo. The residue is purifiedby chromatography eluting with ethyl acetate. The filtrate is thenconcentrated in vacuo and triturated with diethylether to give acompound of formula (I), wherein a is 1, R³is O and R⁴ is H, as a solid.

[0111] Referring to Scheme 2 that follows, compounds of formula (I),wherein a is 1, R³ O and R⁴ is H, may also be prepared by coupling acompound of formula (II) with an acid of formula (IV) in the presence ofan activating agent, such as a carbodiimide, and a hindered organicamine base, such as DMAP, in a suitable aprotic solvent, such as DMF.Such couplings are described in many organic texts such as ‘Principlesof Peptide Synthesis’ by Miklos Bodanszky (Springer Verlag, 1984)chapter 2, incorporated herein by reference. In one embodiment of Scheme2, polymer supported carbodiimide (available from Argonaut Technologies,Inc.) is added to a solution comprising a compound of formula (II), DMAPand an acid of formula (IV) in DMF/DCM. The reaction mixture is thenshaken at ambient temperature for about 18 h. The reaction mixture isthen filtered and the resin is washed with DCM. The combined filtrateand washings are subject to an amino propyl SPE cartridge. Impuritiesare removed by elution with methanol and the desired product is removedby elution with methanol/acetic acid. The product filtrate isconcentrated in vacuo and then triturated with methanol to give acompound of formula (I), wherein a is 1, R³ is O and R⁴ is H, as asolid.

[0112] Compounds of formula (I) wherein R³ is H may be synthesised in amanner analogous to Scheme 1 or 2. In this case, compounds of formula(II) are first converted to compounds corresponding to those of formula(II) wherein one of the C═O groups is converted to CH₂ via reductionwith a suitable reducing agent. A suitable reducing agent is sodiumborohydride in methanol followed by TFA and triethylsilane.

[0113] Acid chlorides of formula (III) and acids of formula (IV) areeither known compounds or may be prepared by literature methods such asthose described in ‘Advanced Organic Chemistry’ by Jerry March, fourthedition (John Wiley & Sons, 1992) page 1269 column 2, and page 1280column 2, incorporated herein by reference.

[0114] It will be appreciated by those persons skilled in the art thatcompounds of formula (I) may be prepared by interconversion, utilisingother compounds of formula (I) as precursors. In particular, alkylationsare well known to those skilled in the art and are described in manystandard organic chemistry texts such as ‘Advanced Organic Chemistry’.For example, compounds of formula (I) wherein R⁴ is C₁₋₆alkyl can beprepared by alkylating compounds of formula (I) wherein R⁴ is H.Suitable alkylating agents include C₁₋₆alkyl iodides.

[0115] As will be appreciated by those skilled in the art, it may benecessary or desirable at any stage in the synthesis of compounds offormula (I) to protect one or more sensitive groups in the molecule soas to prevent undesirable side reactions. The protecting groups used inthe preparation of compounds of formula (I) may be used in conventionalmanner. See, for example, those described in ‘Protective Groups inOrganic Synthesis’ by Theodora W Green and Peter G M Wuts, secondedition (John Wiley and Sons, 1991), incorporated herein by reference,which also describes methods for the removal of such groups.

[0116] Compounds of formula (II) may, for example, be prepared accordingto Scheme 3 that follows.

[0117] Compounds of formula (V) may, for example, be prepared accordingto Scheme 4 that follows.

[0118] Phthalates of formula (IX) are either known compounds or may beprepared by conventional chemistry from commercially available startingmaterials.

[0119] 4-Nitrobenzyl chlorides of formula (XII) are either knowncompounds or may be prepared by conventional chemistry from commerciallyavailable starting materials.

[0120] Compounds of formula (I) wherein a=0, may be synthesised in ananalogous manner. In this case the compounds analogous to those offormula (V) but not possessing the CHR¹¹ moiety are commerciallyavailable thus rendering Scheme 4 unnecessary.

[0121] Certain intermediates described above are novel compounds, and itis to be understood that all novel intermediates herein form furtheraspects of the present invention.

[0122] Solvates (e.g. hydrates) or salts of a compound of the inventionmay be formed during the work-up procedure of any one of theaforementioned process steps.

[0123] The Intermediates and Examples that follow illustrate theinvention but do not limit the invention in any way. All temperaturesare in ° C. ¹H nmr spectra were obtained at 400 MHz on a Bruker DPX400.Mass directed autopurification was performed using a system comprising aHP1100 HPLC, a Gilson Aspec Autosampler, a HP1050 Make up Pump, aMicromass Platform Mass Spectrometer, a LC Packings Prep AccurateCombi-Chem Flow Processor (ACM-01-10), a Supelco 5 um ABZ+5 cm×10 mm IDColumn and a Gilson Fraction Collector. The samples were dissolved in50:50 acetonitrile:dimethylsulfoxide. A suitable gradient elutiondetermined on the basis of the retention time of the compound in LC/MSwas employed, for example 20-50% acetonitrile or 30-60% acetonitrile inwater. The determination of such gradient elutions will be appreciatedby those skilled in the art.

Intermediate 1 Ethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate

[0124] Sodium (60 g, 2.6 mol) was dissolved in ethanol (1.21) and themixture was cooled to 40° C. Diethylphthalate (960 ml, 4.83 mol) wasadded and the mixture heated under nitrogen until the temperaturereached 115° C. Diethyl succinate (211.3 g, 1.21 mol) was added dropwiseover 45 min. The reaction was heated at 115° C. for a further 45 min,cooled to room temperature and poured onto water (1.2 l). Ethyl acetate(1 l) was added and stirred, the layers were separated and the organicswere extracted with sodium hydroxide solution (2N, 1 l). The combinedaqueous was acidified to pH 3 and the mixture extracted with ethylacetate (2×1 l). The combined organics were washed with a saturatedsolution of sodium hydrogen carbonate (2×1.5 l), then brine, dried(MgSO₄), filtered and the solvent evaporated under vacuum. The residuewas purified using a 2.5 kg Biotage column eluting with 5% ethylacetate/hexane to give the title compound as a white solid, (60 g, 16%).δH CDCl₃ 10.44,(2H, s), 8.34,(2H, m), 7.68,(2H, m), 4.37,(4H, q),1.37,(6H, t).

Intermediate 2 Ethyl 1,4-diethoxy-2,3-naphthalenedicarboxylate

[0125] Ethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate (30 g, 98.6mmol) and potassium carbonate (150 g, 1.09 mmol) were stirred in acetone(600 ml) under nitrogen. Iodoethane (150 g, 0.96 mol) was added and themixture was stirred at reflux overnight. The reaction was cooled,diluted with ethyl acetate and filtered. The filtrate was evaporated toleave a brown oil, which was dissolved in toluene and washed withpotassium hydroxide solution (5%, 150 ml) and brine. Drying overmagnesium sulphate and evaporation of the solvent gave a yellow solid.Purification using an 800 g Biotage column gave the title compound as awhite solid (32 g, 90%). δH CDCl₃ 8.16,(2H, m), 7.60,(2H, m), 4.40,(4H,q), 4.18,(4H, q), 1.50,(6H, t), 1.40,(6H, t).

Intermediate 3 1,4-Diethoxy-2,3-naphthalenedicarboxylic acid

[0126] Ethyl 1,4diethoxy-2,3-naphthalenedicarboxylate (32 g, 89 mmol)was added to a solution of sodium hydroxide (20 g) in ethanol (200 ml)and water (40 ml) and stirred for 1.5 h at 60° C. The reaction wascooled and the thick white suspension was filtered. The solid wasdissolved in a mixture of ethyl acetate (200 ml) and water (800 ml). Thelayers were separated and the aqueous was acidified with hydrochloricacid (2M_(,) 120 ml). The aqueous was extracted with ethyl acetate (2×)and the combined organics were dried (MgSO₄). Evaporation of the solventunder vacuum gave the title compound as a white solid (25 g, 92%). δH[²H₆]-DMSO 13.26,(2H, s), 8.15,(2H, m), 7.72,(2H, m), 4.13,(4H, q),1.42,(6H, t).

Intermediate 4 4-nitrobenzyl imidothiocarbamate hydrochloride

[0127] A mixture of 4-nitrobenzylchloride (Aldrich, 85.8 g, 0.5 mol) andthiourea (Aldrich, 38.1 g, 0.5 mol) in ethanol (250 ml) was heated toreflux, under nitrogen, for 2.5 h. The reaction mixture was allowed tocool to ambient temperature and the precipitate was filtered off. Thesolid was washed with ethanol and diethylether and then dried in vacuoto give the title compound as a white solid (112.4 g, 90.8%). δH[²H₆]-DMSO 4.72 (2H, s); 7.74 (2H, d, 9.4 Hz); 8.25 (2H, d, 9.4 Hz);9.41 (3H, bds).

Intermediate 5 4-Nitro-benzylsulfonamide

[0128] Through a solution of Intermediate 4 (112.4 g, 0.45 mol) in water(2400 ml) was bubbled chlorine gas for 6 h at <12° C. The reactionmixture was extracted with ethyl acetate (×2) and the combined organicphases washed with water and brine. The precipitate, which formed onstanding, was filtered off and discarded. The filtrate was concentratedin vacuo to give a oily yellow solid (70 g). This solid was addedportionwise, with cooling, to 0.880 ammonia (450 ml). The mixture wasstirred at ambient temperature for 1.5 h and then diluted with water(750 ml). The resultant precipitate was filtered off, washed with waterand dried in vacua to give a pale yellow solid (25.5 g). This was heatedin acetonitrle and filtered whilst hot. The filtrate was concentrated invacuo and dried to give the title compound as a white solid (17.53 g,18%). δH [²H6]-DMSO 4.48 (2H, s); 6.99 (2H, s); 7.66 (2H, d, 9.5 Hz);8.23 (2H, d, 9.5 Hz).

Intermediate 6 4-Amino-benzylsulfonamide

[0129] To 10% palladium on charcoal catalyst (3 g, 50% wet with water)under a nitrogen atmosphere was added a solution of4-nitro-benzylsulfonamide (17.53 g, 81.1 mmol). in dimethylformamide(175 ml). The atmosphere of nitrogen was replaced with hydrogen and themixture stirred vigourously for 5 h. The atmosphere was replaced withnitrogen and the mixture filtered through celite. The solvent wasremoved in vacuo and the residue triturated with diethylether to give adark brown solid (14.7 g). The solid was heated in acetonitrile (440 ml)and filtered whilst hot (to remove excess catalyst). The filtrate wasallowed to cool and the precipitate filtered off and dried in vacuo togive the title compound as a beige solid (12.32 g, 82%). δH [²H₆]-DMSO4.05 (2H, s); 5.11 (2H, s); 6.53 (2H, d, 8.2 Hz); 6.63 (2H, s); 7.01(2H,d, 8.2 Hz).

Intermediate 71-[4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]methanesulfonamide

[0130] To a solution of 1,4-diethoxy-2,3-naphthalenedicarboxylic acid(0.75 g, 2.5 mmol, 1.1 eqs) in glacial acetic acid (5 ml) was added4-amino-benzylsulfonamide (0.43 g, 2.3 mmol). The reaction mixture washeated at 120° C. for 18 h. The reaction mixture was allowed to cool toambient temperature and then poured into water (5 ml). The precipitatewas filtered off, triturated with ethyl acetate/40:60 petroleum etherand then dried in vacuo to give the title compound as a beige solid (790mg, 69%). δH [²H₆]-DMSO 1.48 (6H, t); 4.40 (2H, s); 4.52 (4H, q); 7.00(2H, s); 7.51 (2H, d, 8.5Hz); 7.56 (2H, d, 8.5 Hz); 7.89 (2H, m); 8.43(2H, m)

Intermediate 81-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]methanesulfonamide

[0131] Sodium borohydride (0.5M solution in 2-methoxy ethyl ether, 56ml, 23 mmol, 3.5 eqs) was added portionwise over 2 h to a suspension ofIntermediate 7 (3 g, 6.6 mmol) in anhydrous methanol (60 ml) keeping thetemperature below 0° C. The reaction mixture was stirred under nitrogenat 0° C. for a further 0.5 h. The reaction was quenched with saturatedammonium chloride solution (50 ml) and extracted with ethylacetate (×3).The combined organic extracts were dried (Na₂SO₄) and then concentratedin vacuo to give a pale yellow solid/oil. The solid/oil was addedportionwise to trifluoroacetic acid (15 ml) at 0° C. Triethylsilane(1.48 ml, 9.3 mmol, 1.4 eqs) was added and stirring continued at 0° C.for 10 mins. The temperature was allowed to reach ambient and stirringcontinued for a further 10 mins. The reaction mixture was concentratedin vacuo and the residue triturated with diethylether to give the titlecompound as a pink solid (2.3 g, 79%). δH [²H₆]-DMSO 1.44 (3H, t); 1.50(3H, t); 4.27 (2H, m); 4.30 (2H, q); 4.38 (2H, q); 5.18 (2H, s); 6.85(2H, s); 7.43 (2H, d, 9Hz); 7.57-7.75

EXAMPLE 11-[4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-(phenylacetyl)methanesulfonamide

[0132] To a solution of Intermediate 7 (40 mg, 0.088 mmol) andphenylacetyl chloride (77 mg, 0.5 mmol, 5.7eqs) in acetone (3.5 ml) wasadded potassium carbonate (100 mg, 0.72 mmol, 8.2 eqs). The reactionmixture was heated at 80° C. under nitrogen for 18 h. The reaction wasallowed to cool to ambient temperature and then filtered to removeremaining solid. The filtrate was acidified using 2N hydrochloric acidand then diluted with water. The precipitate was filtered off and thentriturated with diethylether to give the title compound as a beige solid(22 mgs, 43%). MH⁺573.

[0133] The examples of Table 1 were prepared in the manner described forExample 1. TABLE 1

Ex a b R¹ R³ R⁵ R⁶ R¹² MH⁺ 2 1 1 H O H H 4-methoxyphenyl 603 3 1 0 H O —— 4-cyanophenyl 584 4 1 0 H O — — phenyl 559 5 1 0 H O — —3-fluorophenyl 577 6 1 0 H O — — 4-nitrophenyl 604 7 1 0 H O — —4-fluorophenyl 577 8 1 0 H O — — methyl 497 9 1 0 H O — — n-butyl 539 101 0 H O — — t-butyl 539 11 1 0 H O — — cyclohexyl 565 12 1 1 H O H HOC(O)CH₃ 555 13 1 0 H O — — napth-2-yl 609 14 1 0 H O — —5-methyl-1,2-oxazol-5-yl 564 15 1 2 H O H H phenyl 587 16 1 2 H O H Hcyclohexyl 593 17 1 0 H O — — furan-2-yl 549

EXAMPLE 181-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-(phenylacetyl)methanesulfonamide

[0134] To a solution of Intermediate 8 (176 mg, 0.4 mmol)) andphenylacetyl chloride (210 mg, 1.36 mmol, 3.4 eqs) in toluene (16 ml)was added 4-dimethylaminopyridine (100 mg, 0.8 mmol, 2 eqs). Thereaction mixture was heated at 120° C. under nitrogen for 18 h. Thereaction was allowed to cool to ambient temperature and thenconcentrated in vacuo. The residue was purified on a silica gel SPEcartridge eluting with ethylacetate. The filtrate was concentrated invacuo and then triturated with diethylether to give the title compoundas a cream solid (130 mg, 57.5%). MH⁺559.

[0135] The examples of Table 2 were prepared in the manner described forExample 18. TABLE 2

Ex a b R¹ R³ R⁵ R⁶ R¹² MH⁺ 19 1 1 H H H H 3,4-dichlorophenyl 627 20 1 1H H H H 4-methylphenyl 573 21 1 1 H H H H 2-methylphenyl 573 22 1 1 H HMe Me phenyl 587 23 1 1 H H H H 4-i-butylphenyl 615 24 1 1 H H H H4-methoxyphenyl 617 25 1 1 H H H H 3-fluorophenyl 577 26 1 1 H H H H3-methylphenyl 573 27 1 1 H H H H 4-i-propylphenyl 601 28 1 1 H H H H4-ethylphenyl 587 29 1 1 H H H H 2-chlorophenyl 593 30 1 1 H H H H4-phenylphenyl 635 31 1 1 H H H H 2-methoxyphenyl 589 32 1 1 H H H H2-fluorophenyl 577 33 1 1 H H H H 4-trifluoromethylphenyl 627 34 1 1 H HH H 2,3-dimethoxyphenyl 619 35 1 1 H H H H 4-hydroxyphenyl 575 36 1 1 HH H H 2,5-dimethoxyphenyl 619 37 1 1 H H H H 4-dimethylaminophenyl 60238 1 1 H H H H 3,4-dimethoxyphenyl 619 39 1 1 H H H H 2,5-dimethylphenyl587 40 1 1 H H Me H 4-i-butylphenyl 629 41 1 1 H H H H 2-benzyloxyphenyl665 42 1 1 H H H H 3-benzyloxyphenyl 665 43 1 1 H H H H 3-methoxyphenyl589 44 1 1 H H H H 2-(CH₂CO₂H)phenyl 617 45 1 1 H H H H 4-(CO₂Me)phenyl617 46 1 1 H H H H 4-(SO₂NMe₂)phenyl 666 47 1 1 H H H H2-(CH₂CO₂Me)phenyl 631 48 1 1 H H H H naphth-2-yl 609 49 1 0 H H — —

571 50 1 1 H H cyclopropyl phenyl 585 51 1 1 H H H H thiophen-3-yl 56552 1 1 H H H H pyridin-3-yl 560 53 1 1 H H H H thiophen-2-yl 565 54 1 1H H H H pyridin-2-yl 560 55 1 1 H H H H pyridin-4-yl 560 56 1 1 H H H H2-methyl-1,3-thiazol-4-yl 580 57 1 1 H H H H4-methyl-1,2,5-oxadiazol-3-yl 565 58 1 1 H H H H5-methyl-1,2-oxazol-3-yl 564 59 1 1 H H H H 3-methyl-1,2-oxazol-5-yl 56460 1 1 H H H H 4-methyl-1,3-thiazol-5-yl 580

[0136] The examples of Table 3 were prepared in the manner described forExample 18 except Intermediate 8 was replaced with intermediate 7. TABLE3

Ex a b R¹ R³ R⁵ R⁶ R¹² MH⁺ 61 1 1 H O H H 2-methylphenyl 587 62 1 1 H OH H 4-fluorophenyl 591 63 1 1 H O H H 3-methoxyphenyl 603 64 1 1 H O EtH phenyl 601 65 1 1 H O H H 3-fluorophenyl 591 66 1 1 H O H H3,4-dimethoxyphenyl 633 67 1 1 H O H H 4-methylphenyl 587 68 1 1 H O MeH phenyl 587 69 1 1 H O H H 2,5-difluorophenyl 609 70 1 1 H O H H4-chlorophenyl 607 71 1 1 H O H H 2-methoxyphenyl 603 72 1 1 H O H H2,6-dimethylphenyl 601 73 1 1 H O Me Me 3-methylphenyl 615 74 1 1 H O HH 3-fluoro-4-methylphenyl 605 75 1 1 H O Cl H phenyl 607 76 1 1 H O H Hnaphth-1-yl 623 77 1 1 H O H H naphth-2-yl 623 78 0 0 H O — — methyl 555

EXAMPLE 791-[4-(4,9-diethoxy-1-oxo-1,3dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-[(4-methyl-1,3-thiazol-5-yl)acetyl]methanesulfonamide

[0137] To a solution of Intermediate 8 (44 mg, 0.1 mmol),1-[4-methyl-1,3-thiazol-5-yl]acetic acid (32 mg, 0.2 mmol, 2 eqs) and4-dimethylaminopyridine (74 mg, 0.6 mmol, 6 eqs) in dimethylformamide (2ml) and dichloromethane (2 ml) was added polymer supported carbodiimide(Argonaut Technologies, Inc., 480 mg, 0.45 mmol, 4.5 eqs). The reactionmixture was shaken at ambient temperature for 18 h. The reaction wasfiltered and the resin washed with dichloromethane. The combinedfiltrate and washings were subject to an amino propyl SPE cartridge.Impurities were removed by elution with methanol and the requiredproduct was removed by elution with methanol/acetic acid. The productfiltrate was concentrated in vacuo and then triturated with methanol togive the title compound as a beige solid. MH⁺580.

[0138] The examples of Table 4 were prepared in the manner described forExample 79. TABLE 4

Ex a b R¹ R³ R⁵ R⁶ R¹² MH⁺ 80 1 1 H H H H 4-trifluoromethoxyphenyl 64381 1 1 H H H H 3-trifluoromethoxyphenyl 643 82 1 1 H H H H3,4-diethoxyphenyl 647 83 1 1 H H H H 3,5-dimethoxyphenyl 619 84 1 1 H HH H

603 85 1 1 H H H H

631 86 1 1 H H Me H 6-methoxy-naphth-2-yl 653 87 1 1 H H H H

598 88 1 1 H H H H

599 89 1 1 H H H H

612 90 1 1 H H H H

599 91 1 0 H H — —

603 92 1 0 H H — —

626

[0139] The example of Table 5 was prepared in the manner described forExample 79 except Intermediate 8 was replaced with Intermediate 7. TABLE5

Ex a b R¹ R³ R⁵ R⁶ R¹² MH⁺ 93 1 1 H O H H

617

EXAMPLE 941-[4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-N-[(4-methoxyphenyl)acetyl]-N-methyl-methanesulfonamide

[0140] To a solution of the product of Example 2 (40 mg, 0.066 mmol))and methyl iodide (0.032 ml, 0.51 mmol, 7.7 eqs) in acetonitrile (5 ml)was added sodium carbonate (14 mg, 0.133 mmol, 2 eqs). The reactionmixture was stirred at ambient temperature under nitrogen for 18 h. Thereaction was concentrated in vacuo and then partioned betweenethylacetate (20 ml) and 2N hydrochloric acid (20 ml). The organic phasewas washed with brine, dried (MgSO₄) and then concentrated in vacuo. Theresidue was preabsorbed onto silica and purified on a silica gel SPEcartridge eluting with an ethylacetate/petroleum ether gradient. Thesolvent was removed in vacuo to give the title compound as a yellowsolid (15 mg, 36%). MH+617.

[0141] Biological Data

[0142] The ability of the compounds to bind to EP4 receptors may bedemonstrated in the Human EP₄ Scintillation Proximity Assay.

[0143] Quantification of radioligand binding by scintillation proximityassay (SPA) is a long-established principle. Briefly, the affinity ofcompounds for a receptor is assessed by the specific competition betweenknown quantities of radiolabelled ligand and compound for that receptor.Increasing concentrations of compound reduce the amount of radiolabelthat binds to the receptor. This gives rise to a diminishingscintillation signal from SPA beads coated with membranes that bear thereceptor. The signal may be detected with a suitable scintillationcounter and the data generated may be analysed with suitablecurve-fitting software.

[0144] The human EP₄ SPA assay (hereafter referred to as ‘the assay’)utilises membranes prepared from Chinese Hamster Ovary (CHO cells)infected with Semliki Forest Virus (SFV). Genetically engineered SFV-1viral particles containing the genetic sequence of the human EP4receptor were used to infect CHO cells resulting in expression of thereceptor protein in cellular membranes. Cells washed free of media arehomogenised in a pH-buffered medium containing peptidase inhibitors. Asuitable buffer is of the following composition: 50 mM HEPES, 1 mM EDTA,25 μg/ml bacitracin, 100 μM leupeptin, 1 mM PMSF, 2 μM Pepstatin A, pHadjusted to 7.4 with KOH. Following removal of cell debris by alow-speed centrifugation, a pellet of membranes is prepared by ahigh-speed (48000 g) centrifugation of the resulting supernatant.Membrane suspensions such as that described may be stored at −80° C.until used.

[0145] For assay, membranes expressing human EP₄ receptors are dilutedin a pH-buffered medium and mixed with SPA beads coated with a suitablesubstance to facilitate the adhesion of membranes to the beads. Theconcentrations of membrane protein and SPA beads chosen should result inSPA binding signal of at least 300 corrected counts per minute (CCPM)when tritiated radioligand at a concentration close to its K_(d)(affinity value) is combined with the mixture. Non-specific binding(nsb) may be determined by competition between the radiolabelled ligandand a saturating concentration of unlabelled ligand. In order toquantify the affinity of EP4 receptor ligands, compounds are diluted ina stepwise manner across the wells of a 96-well plate. Radioligand,compound, and unlabelled ligand are then added to a 96-well platesuitable for the measurement of SPA binding signals prior to theaddition of bead/membrane mixture to initiate the binding reaction.Equilibrium may be achieved by incubation at room temperature for 120minutes prior to scintillation counting. The data so generated may beanalysed by means of a computerised curve-fitting routine in order toquantify the concentration of compound that displaces 50% of thespecific radioligand binding (IC₅₀). The affinity (pK_(i)) of thecompound may be calculated from the IC₅₀ by application of theCheng-Prusoff correction. Suitable reagents and protocols are: reactionbuffer containing 50 mM HEPES, 10 mM MgCl₂, pH adjusted to 7.4 with KOH;SPA beads coated with wheatgerm agglutinin; 1.25 nM [³H]-prostaglandinE₂ as radioligand; 10 μM prostaglandin E₂ as unlabelled ligand; athree-fold dilution series of compound starting at 10 μM and ending at0.3 nM is adequate.

[0146] The ability of the compounds to antagonise EP4 receptors may bedemonstrated in the [¹²⁵I]cAMP Scintillation Proximity Assay (hereafterreferred to as ‘the cAMP assay’). The cAMP assay utilises HEK-293 cellsexpressing the recombinant human EP4 receptor, obtained from ReceptorBiology, Inc. Beltsville, Md., USA. The cells are cultured in Dulbecco'sModified Eagle Medium—HAM F12 mix (DMEM-F12), containing 10% heatinactivated-foetal bovine serum (FBS) and 2 mM L-glutamine. The cellsare either passaged into fresh medium or used in an assay once 90%confluency as determined visually had been achieved.

[0147] The cells are harvested by treatment with Versene, re-suspendedin fresh culture medium and plated out to yield approximately 10,000cells per well of a 96-well plate for overnight culture in culturemedium additionally supplemented with 3 μM indomethacin. For assay, theculture medium is replaced with assay medium (DMEM-F12 containing 300 μMisobutylmethylxanthine (IBMX) and 3 μM indomethacin) and incubated for30 minutes. Following this, antagonist is then added at variousconcentrations such that an entire agonist concentration-effect curvecan be obtained in the presence of a single concentration of theantagonist. The antagonist is allowed to equilibrate with the cells for30 minutes. Subsequently the cells are challenged with an agonist for 15minutes. The reaction is stopped by the aspiration of the assay mediumand the addition of ice-cold ethanol. All incubations are carried out at37° C. in a 5% carbon dioxide atmosphere. Care must be taken to ensurethe constancy of IBMX, indomethacin and vehicle (DMSO) concentrationsthroughout. The amount of cAMP in each well is then determined by[¹²⁵I]cAMP scintillation proximity assay using a proprietary kit,obtained from Amersham, Buckinghamshire, UK, and according to themanufacturer's instructions.

[0148] Data from cAMP assays are expressed as pmol cAMP per well. Afour-parameter logistic equation of the form:

E=((Em.[A]){circumflex over ( )}nH)/((EC ₅₀ {circumflex over( )}nH)+([A]{circumflex over ( )}nH))

[0149] is then fitted to E/[A] curve data in order to estimate maximumeffect (Em), curve mid-point (EC50), and Hill slope (nH); other terms inthe equation are effect (E) and concentration ([A]). Individualestimates of curve parameters are obtained from each curve. An empiricalestimate of antagonist affinity (pA₂) could then be obtained using thefollowing formula:

pA ₂=log((EC ₅₀ ^(B) /EC ₅₀ ^(A))−1)−log[B]

[0150] where EC₅₀ ^(A) is the midpoint of a control agonistconcentration-effect curve in the absence of antagonist; EC₅₀ ^(B) isthe midpoint of an agonist concentration effect curve produced in thepresence of a fixed concentration of antagonist; and [B] is theconcentration of antagonist used. Estimates from individual experimentsare then averaged to provide mean data. Quoted values are therefore themean±standard deviation (s.d.) of n separate experiments, each derivedfrom a separate cAMP assay.

[0151] For the rigorous estimation of antagonist affinity values(pK_(b)) the method of Arunlakshana and Schild is employed. Briefly, themidpoint of agonist concentration/effect curves in the presence andabsence of antagonist are used to calculate concentration ratios (CR).Linear regression is performed on a plot of (CR-1) against concentrationof antagonist (−log[B]) in order to estimate the point of intersectionwith the concentration (−log[B]) axis and the slope of the line. If theslope of the regression does not differ significantly from unity then itmay be constrained to 1.0. Under this latter circumstance, the point ofintersection on the concentration axis represents the affinity (pK_(b))of the antagonist.

[0152] The following examples have a pK4 of 7.0 or greater at EP4receptors as determined using the above-mentioned procedure:

[0153] 1, 2, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34,36, 38, 39, 40, 42, 43, 47, 48, 50, 51, 60, 61, 62, 63, 64, 65, 66, 67.,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 80, 81, 82, 83, 84, 85, 86, 87,88, 92 and 93.

1. Compounds of formula (I)

and pharmaceutically acceptable derivatives thereof in which: a=0 or 1;b=0 to 3; R¹ is H, halogen, C₁₋₆alkyl, S—C₁₋₆alkyl, C₁₋₆alkoxy, OCF₃,OCH₂CF₃, O-cyclopropyl, OCH₂-cyclopropyl, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, NO₂, OH, CH₂OC₁₋₆alkyl or CH₂OH; each R² is independentlyselected from C₁₋₄alkyl; R³ is H or O; R⁴ is H or C₁₋₆alkyl; R⁵ and R⁶are each independently selected from H halogen, C₁₋₃alkyl, or are takentogether to form a cyclopropyl ring; R⁷ to R¹⁰ are each independentlyselected from H, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one ormore fluorine atoms, O-cyclopropyl, OCH₂-cyclopropyl, S—C₁₋₆alkyl, NH₂,NHC₁₋₆alkyl, N(C₁₋₆alkyl)₂, halogen, NO₂, OH, CH₂OC₁₋₆alkyl, CH₂OH; R¹¹is selected from H, OH, halogen, dihalogen, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, C₁₋₆alkyl, C₁₋₆dialkyl, C₁₋₆alkoxy, NHCO(C₁₋₆alkyl), or═O; R¹² is selected from H, C₁₋₆alkyl, phenyl, phenyl substituted by oneor more R¹³, phenyl fused to a heterocycle, naphthyl, naphthylsubstituted by one or more R₁₃, C₄₋₇cycloalkyl, C₄₋₇cycloalkyl fused toa benzene ring, OCOC₁₋₆alkyl, heteroaryl or heteroaryl substituted byone or R¹³; R¹³ is halogen, C₁₋₆alkyl, C₁₋₆alkyl substituted by one ormore fluorine atoms, C₁₋₆alkoxy, C₁₋₆alkoxy substituted by one or morefluorine atoms, phenyl, CN, CO₂H, CO₂C₁₋₆alkyl, OH, NH₂, NHC₁₋₆alkyl,N(C₁₋₆alkyl)₂, S(O)_(n)C₁₋₆alkyl where n is 0, 1 or 2, SO₂N(C₁₋₆alkyl)₂,CONH₂, CONHC₁₋₆alkyl, CON(C₁₋₆alkyl)₂, COC₁₋₆alkyl, benzyloxy, CH₂CO₂H,CH₂CO₂C₁₋₆alkyl, NO₂ or NHCO(C₁₋₆alkyl);

 is a single bond or, when R³ is O, a double bond.
 2. Compounds asclaimed in claim 1 wherein a=1.
 3. Compounds as claimed in claim 1 or 2wherein b=1.
 4. Compounds as claimed in any one of claims 1 to 3 whereinR¹ is H or bromine.
 5. Compounds as claimed in any one of claims 1 to 4wherein each R² is ethyl.
 6. Compounds as claimed in any one of claims 1to 5 wherein R⁴ is H or methyl.
 7. Compounds as claimed in any one ofclaims 1 to 6 wherein R⁵ and R⁶ are each independently selected from H,chlorine, methyl or ethyl, or are taken together to form a cyclopropylring.
 8. Compounds as claimed in any one of claims 1 to 7 wherein eachof R⁷ to R¹¹ is H.
 9. Compounds as claimed in any one of claims 1 to 8wherein R¹ is at the 6-position of the naphthalene ring, as defined informula (I).
 10. A compound of formula (I) as claimed in claim 1 and asnamed in any one of Examples 1 to
 94. 11. A process for the preparationof compounds of formula (I) and pharmaceutically acceptable derivativesthereof as defined in any of claims 1 to 10, which comprises: (A),coupling a sulfonamide of formula (II)

or a protected derivative with an acid chloride of formula (III)

or a protected derivative thereof; or (B), coupling a sulfonamide offormula (II)

or a protected derivative thereof with an acid of formula (IV)

or a protected derivative thereof; or (C), interconversion of a compoundof formula (I) into another compound of formula (I); or (D),deprotecting a protected derivative of compound of formula (I); andoptionally converting compounds of formula (I) prepared by any one ofthe processes (A) to (D) into pharmaceutically acceptable derivativesthereof.
 12. A pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable derivative thereof asdefined in any one of claims 1 to 10 in admixture with one or morephysiologically acceptable carriers or excipients.
 13. A compound offormula (I) or a pharmaceutically acceptable derivative thereof asdefined in any one of claims 1 to 10 for use in human or veterinarymedicine.
 14. A method of treating a human or animal subject sufferingfrom a condition which is mediated by the action of PGE₂ at EP4receptors, which method comprises administering to said subject aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof as defined in any one of claims 1 to 10.15. The use of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof as defined in any one of claims 1 to 10for the manufacture of a therapeutic agent for the treatment of acondition which is mediated by the action of PGE₂ at EP4 receptors.